Therapeutic 1,4-thiazepines

ABSTRACT

Compounds of formula I ##STR1## in which n=0, 1 or 2; 
     R 1 , R 2 , R 6  and R 7  independently represent H or alkyl (optionally substituted by one or more halo); 
     R 3  and R 4  independently represent H or alkyl or together represent a group of formula ═NR 12  where R 12  represents H, hydroxy, alkyl, phenyl or alkoxy; each alkyl, phenyl and alkoxy being optionally substituted with one or more halo; 
     R 5  represents: (a) H, (b) alkyl, (c) a group of formula --COR 13  in which R 13  is H, alkyl or phenyl, when R 3  and R 4  represent H or alkyl (optionally substituted with one or more halo), or (d) a group of formula --S(O) p  R 14  in which p=1 or 2 and R 14  is alkyl or phenyl, when R 3  and R 4  represent H or alkyl (optionally substituted with one or more halo); each alkyl and phenyl optionally substituted with one or more halo; 
     and R 8  to R 11  independently represent H, halo, cyano, nitro, alkyl alkoxy, alkanoyl, carboxy, alkanoyloxy, carbamoyl (optionally substituted with alkyl or sulphamoyl (optionally substituted with alkyl of 1 to 4 carbon atoms); each alkyl, alkoxy, alkanoyl or alkanoyloxy optionally substituted with one or more halo; 
     have utility in the treatment of seizures and/or neurological disorders such as epilepsy and/or as neuroprotective agents to protect against conditions such as stroke.

This application is a 371 of PCT/EP93/03123 filed Nov. 6, 1993. Priorityis also claimed of British applications GB 9223441.8 and GB 9223443.4,both filed 9 Nov. 1992.

This invention relates to derivatives of2,3,4,5-tetrahydro-1,4-benzothiazepines, to pharmaceutical compositionscontaining them, to processes for their preparation and to their use inthe treatment of seizures and/or neurological disorders such as epilepsyand/or as neuroprotective agents to protect against conditions such asstroke.

In particular the present invention provides compounds of formula I##STR2## in which: n=0, 1 or 2

R₁, R₂, R₆ and R₇ independently represent H or alkyl of 1 to 4 carbonatoms (optionally substituted with one or more halo);

R₃ and R₄ independently represent H or alkyl of 1 to 4 carbon atoms; ortogether represent a group of formula ═NR₁₂ where R₁₂ represents H,hydroxy, alkyl of 1 to 4 carbon atoms, phenyl or alkoxy of 1 to 4 carbonatoms; each alkyl, phenyl and alkoxy being optionally substituted withone or more halo;

R₅ represents: (a) H, (b) alkyl of 1 to 4 carbon atoms, (c) a group offormula --COR₁₃ in which R₁₃ represents H, alkyl of 1 to 4 carbon atomsor phenyl, when R₃ and R₄ represent H or alkyl (optionally substitutedwith one or more halo), or (d) a group of formula --S(O)_(p) R₁₄ inwhich p=1 or 2 and R₁₄ is alkyl of 1 to 4 carbon atoms or phenyl, whenR₃ and R₄ represent H or alkyl (optionally substituted with one or morehalo); each alkyl and phenyl being optionally substituted with one ormore halo;

R₈ to R₁₁ independently represent H, halo, cyano, nitro, alkyl of 1 to 4carbon atoms, alkoxy of 1 to 4 carbon atoms, alkanoyl of 1 to 4 carbonatoms, carboxy, alkanoyloxy of 1 to 4 carbon atoms, carbamoyl(optionally substituted with alkyl of 1 to 4 carbon atoms) or sulphamoyl(optionally substituted with alkyl of 1 to 4 carbon atoms); each alkyl,alkoxy, alkanoyl and alkanoyloxy being optionally substituted with oneor more halo;

their stereoisomers; and

pharmaceutically acceptable salts thereof;

with the provisos that:

(i) when n=0; at least one of R₁ to R₁₁ is other than H;

(ii) when n=0, 1 or 2; R₁, R₂ and R₃ are independently H or alkyl; R₄and R₆ are both H; R₅ is H, alkyl or alkanoyl; and one of R₈ or R₉ andone of R₉ to R₁₀ are separately H, halo, nitro, alkyl, alkoxy ortrifluoromethyl, the remainder of R₈ to R₁₁ being H; R₇ is other thanalkyl;

have utility in the treatment of seizures and/or neurological disorderssuch as epilepsy and/or as neuroprotective agents to protect againstconditions such as stroke.

Compounds of formula I where n=0; R₁ to R₄, R₆ to R₈ and R₁₁ are all H;R₅ is H or acetyl; and R₉ and R₁₀ are both methoxy; are known from Szaboet al, Chem. Ber., 119, pages 2904-2913, (1986).

Compounds of formula I where n=0 or 2; R₁ to R₆, R₈ and R₁₁ are all H;R₇ is methyl; and R₉ and R₁₀ are both methoxy; are known from J. Org.Chem., 30 (8), pages 2812-2818, (1965), (Eng).

Compounds of formula I where n=0; R₁, R₂, R₅, R₆ and R₇ are all H; R₃ isa straight chain alkyl of 1 to 4 carbon atoms; R₄ is a straight chainalkyl of 2 to 4 carbon atoms; and R₈ to R₁₁ are independently H, halo,nitro, alkyl of 1 to 4 carbon atoms (optionally substituted by one ormore halo) or alkoxy of 1 to 4 carbon atoms (optionally substituted byone or more halo); are known as intermediates in the preparation of thecompounds claimed in International patent application WO 93/16055(Wellcome) (see formula XIV, page 18).

Compounds of formula I where n=0, 1 or 2; R₁, R₂ and R₃ areindependently H or alkyl of 1 to 4 carbon atoms; R₄ and R₆ are both H;R₅ is H, alkyl of 1 to 4 carbon atoms or alkanoyl of 1 to 5 carbonatoms; R₇ is alkyl of 1 to 4 carbon atoms and one of R₈ or R₉ and one ofR₁₀ or R₁₁ are independently H, halo, nitro, alkyl of 1 to 4 carbonatoms, alkoxy of 1 to 4 carbon atoms, or trifluoromethyl, the remainderof R₈ to R₁₁ being H; are known from French patent application 4916-M(Hoffmann 1a Roche) (corresponding inter alia to AU 409345) and arestated to have pharmaceutical activity as anti-agconvulsants. Theapplication does not contain any pharmaceutical data to support thisstatement.

Compounds of formula I where n=0; R₁ to R₄, R₆ to R₈, R₁₀ and R₁₁ areall H; R₅ is H or bromoacetyl; and R₉ is H or alkoxy of 1 to 3 carbonatoms; are known as intermediates in the preparation of compoundsclaimed in International patent application WO 92/12143 (Kaneko) (seepages 4, 5 and 7) (corresponding to EP 0565721).

Compounds of formula I where n=0 or 1; R₁ to R₄, R₆ and R₇ areindependently H or alkyl of 1 to 4 carbon atoms; R₅ is H, alkyl of 1 to4 carbon atoms or alkanoyl of 1 to 5 carbon atoms; and one of R₈ or R₉and one of R₉ or R₁₀ are separately H, halo, cyano, nitro, alkyl of 1 to4 carbon atoms, alkanoyl of 1 to 5 carbon atoms or alkanoyloxy of 1 to 4carbon atoms the remaining one of R₈ or R₉ being H or chloro and theremaining one of R₉ to R₁₀ being H; are known as Freidel Craftscatalysts from European patent application 0368063 (Bayer) (claimingpriority from DE 3837574 and DE 3837575 and corresponding to US4990707).

Compounds of formula I where n=0; R₁ to R₄ and R₆ to R₁₁ are all H; andR₅ is H or benzoyl; are known from Boudet et al, C. R. Acad. Sci. ParisSeries C, 282, pages 249-251 (26 Jan. 1976).

Compounds of formula I where n=0, R₁ to R₃ and R₆ to R₁₁ are all H; R₄is H or methyl; and R₅ is dichloroacetyl; where n=1 or 2, R₁ to R₃ andR₅ to R₁₁ are all H and R₄ is H or methyl; and salts of compounds offormula I where n=1 or 2, R₁ to R₁₁ are all H; and the salt ishydrochloride salt; are known from Indian J. Chem., 7(9), pages 862-5,(Eng) (in conjunction with Chem. Abs., 71, 124391p, (1969) and Chem.Abs. 8th Coll. Subst. Ind., p4452S).

Therefore the present invention provides novel compounds of formula II##STR3## in which: n=0, 1 or 2; R₁, R₂, R₆ and R₇ independentlyrepresent H or alkyl of 1 to 4 carbon atoms (optionally substituted withone or more halo);

R₃ and R₄ independently represent H or alkyl of 1 to 4 carbon atoms; ortogether represent a group of formula ═NR₁₂ where R₁₂ represents H,hydroxy, alkyl of 1 to 4 carbon atoms, phenyl or alkoxy of 1 to 4 carbonatoms; each alkyl, phenyl and alkoxy being optionally substituted withone or more halo;

R₅ represents: (a) H, (b) alkyl of to 4 carbon atoms, (c) a group offormula --COR₁₃ in which R₁₃ represents H, alkyl of 1 to 4 carbon atomsor phenyl, when R₃ and R₄ represent H or alkyl (optionally substitutedby one or more halo), or (d) a group of formula --S(O)_(p) R₁₄ in whichp=1 or 2 and R₁₄ is alkyl of 1 to 4 carbon atoms or phenyl, when R₃ andR₄ represent H or alkyl (optionally substituted by one or more halo);each alkyl and phenyl being optionally substituted with one or morehalo;

R₈ to R₁₁ independently represent H, halo, cyano, nitro, alkyl of 1 to 4carbon atoms, alkoxy of 1 to 4 carbon atoms, alkanoyl of 1 to 4 carbonatoms, carboxy, alkanoyloxy of 1 to 4 carbon atoms, carbamoyl(optionally substituted with alkyl of 1 to 4 carbon atoms) or sulphamoyl(optionally substituted with alkyl of 1 to 4 carbon atoms); each alkyl,alkoxy, alkanoyl and alkanoyloxy being optionally substituted with oneor more halo;

their stereoisomers; and

pharmaceutically acceptable salts thereof;

with the provisos that:

(A) when n=0; R₁ to R₄, R₆ to R₈ and R₁₁ are all H; R₅ is H or acetyl;and R₉ is methoxy; R₁₀ is other than methoxy;

(B) when n=0 or 2; R₁ to R₆, R₈ and R₁₁ are all H; R₇ is methyl; and R₉is methoxy; R₁₀ is other than methoxy;

(C) when n=0; R₁, R₂, R₅, R₆ and R₇ are all H; R₃ is a straight chainalkyl; and R₈ to R₁₁ are independently H, halo, nitro, alkyl (optionallysubstituted with one or more halo) or alkoxy (optionally substitutedwith one or more halo); R₄ is other than a straight chain alkyl of 2 to4 carbon atoms;

(D) when n=0, 1 or 2; R₁, R₂ and R₃ are independently H or alkyl; R₄ andR₆ are both H; R₅ is H, alkyl or alkanoyl; one of R₈ or R₉ and one ofR₁₀ to R₁₁ are independently H, halo, nitro, alkyl, alkoxy ortrifluoromethyl, the remainder of R₈ to R₁₁ being H; R₇ is other thanalkyl;

(E) when n=0; R₁ to R₄, R₆ to R₈ and R₁₀ to R₁₁ are all H; and R₅ is Hor bromoacetyl; R₉ is other than H or alkoxy of 1 to 3 carbon atoms;

(F) when n=0 or 1; R₁ to R₄, R₆ and R₇ are independently H or alkyl; andone of R₈ or R₉ and one of R₉ or R₁₀ are separately H, halo, cyano,nitro, alkyl, alkoxy, alkanoyl or alkanoyloxy, the remaining one of R₈or R₉ being H or chloro and the remaining one of R₉ to R₁₀ being H; R₅is other than H, alkyl or alkanoyl;

(G) when n=0; and R₁ to R₄ and R₆ to R₁₁ are all H; R₅ is other than Hor benzoyl;

(H) when n=0; R₁ to R₃ and R₆ to R₁₁ are all H; and R₄ is H or methyl;R₅ is other than dichloroacetyl; when n=1 or 2; and R₁ to R₃ and R₅ toR₁₁ are all H; R₄ is other than H or methyl; and when n=1 or 2; and R₁to R₁₁ are all H; the salt of compounds of formula I is other than ahydrochloride salt.

Preferred compounds of formula I or II are those in which (with theprovisos (i) and (ii) above):

n=0 or 1;

R₁, R₂, R₆ and R₇ are independently H or methyl;

R₃ and R₄ are independently H or methyl; or together represent imino,methylimino, phenylimino, hydroxyimino or methoxyimino;

R₅ is H or methyl, and when R₃ and R₄ are H or methyl, R₅ is formyl,acetyl, propionyl, benzoyl, methylsulphinyl, methylsulphonyl orethylsulphonyl; one of R₈ to R₁₁ is H, fluoro, chloro, bromo, iodo,methyl (optionally substituted with one or more halo), methoxy(optionally substituted by one or more halo),nitro, cyano, carboxy,acetyl, dimethylcarbamoyl or dimethylsulphamoyl; the remainder of R₈ toR₁₁ being H;

their stereoisomers; and

pharmaceutically acceptable salts thereof.

More preferred compounds of formula I or II are those in which (with theprovisos (i) and (ii) above):

n=0 or 1;

R₁, R₂, R₆ and R₇ are H; R₃ and R₄ are H; or together are methylimino,phenylimino, hydroxyimino or methoxyimino;

R₅ is H or methyl, and when R₃ and R₄ are H, R₅ is formyl, acetyl,propionyl, benzoyl, methylsulphinyl, methylsulphonyl or ethylsulphonyl;

R₈ is methyl, fluoro or chloro;

R₉ to R₁₁ are all H;

their stereoisomers; and

pharmaceutically acceptable salts thereof.

Specific compounds of formula I or II in which n=0 are:

6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-chloro-4 -methyl -2,3,4,5-tetrahydro-1,4-benzothiazepine;

4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;

4-acetyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;

4-acetyl-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

4-propionyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-chloro-4-propionyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

4-benzoyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-fluoro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-methyl-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

4-ethylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-chloro-4-ethylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;

3-hydroxyimino-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;

3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-chloro-3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;

3-methylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;

6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;

their stereoisomers; and

pharmaceutically acceptable salts thereof.

Specific compounds of formula I or II in which n=1 are:

6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;

4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;

4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;

4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;

6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide;

their stereoisomers; and

pharmaceutically acceptable salts thereof.

It will be understood that a group containing a chain of three or morecarbon atoms may be straight or branched. The term `halo` as used hereinsignifies fluoro, chloro, bromo or iodo.

Certain compounds of formula I or II may form salts with organic orinorganic acids. Reference hereinafter to compounds of formula I or IIincludes all such salts of compounds of formula I or II which arepharmaceutically acceptable. Particularly suitable salts of compounds offormula I or II include, for example, salts with inorganic acids, forexample hydrochlorides, hydrobromides, hydriodides, nitrates, sulphatesand phosphates, salts with organic acids, for example maleates,acetates, citrates, fumarates, tartrates, succinates, benzoates,pamoates, palmitates, methylsulphates, dodecanoates and salts withacidic amino acids such as glutamic acid. It will be appreciated thatsuch salts, provided they are pharmaceutically acceptable, may be usedin therapy in place of the corresponding compounds of formula I or II.Such salts are prepared by reacting the compound of formula I or II witha suitable acid in a conventional manner.

Certain compounds of formula I or II or their salts may exist in morethan one crystal form and the present invention includes each crystalform and mixtures thereof.

Certain compounds of formula I or II or their salts may also exist inthe form of solvates, for example hydrates, and the present inventionincludes each solvate and mixtures thereof.

It will be appreciated by those skilled in the art that certaincompounds of formula I or II contain one or more chiral centres. Thus,for example compounds of formula I or II in which n is 1 contain achiral centre at the sulphur atom; compounds of formula I or II in whichR₁ and R₂ are not identical contain a chiral centre at the 2-carbonatom; compounds of formula I or II in which R₃ and R₄ are not identicalcontain a chiral centre at the 3-carbon atom; and compounds of formula Ior II in which R₆ and R₇ are not identical contain a chiral centre atthe 5-carbon atom. A compound of formula I or II containing a singlechiral centre may exist in two enantiomeric forms. The present inventionincludes each enantiomer of compounds of formula I or II and mixturesthereof.

The enantiomers may be obtained by methods known to those skilled in theart. Such methods typically include:

resolution via formation of diastereoisomeric salts or complexes whichmay be separated, for example, by crystallisation;

formation of diastereoisomeric derivatives or complexes which may beseparated, for example, by crystallisation, gas-liquid chromatography orliquid chromatography, followed by the liberation of the desiredenantiomer from the separated derivative;

selective derivatisation of one enantiomer by reaction with anenantiomer-specific reagent, for example enzymatic esterification,oxidation or reduction, followed by separation of the modified andunmodified enantiomers; or

gas-liquid chromatography or liquid chromatography in a chiralenvironment, for example on a chiral support such as silica with a boundchiral ligand, or in the presence of a chiral solvent.

Alternatively, it may be possible to synthesise a specific enantiomer byasymmetric synthesis using optically active reagents, substrates,catalysts or solvents, or to convert one enantiomer into the other byasymmetric transformation.

When a compound of formula I or II contains more than one chiral centreit may exist in diastereoisomeric forms. The diastereoisomeric pairs maybe separated by methods known to those skilled in the art, for examplechromatography or crystallisation and the individual enantiomers withineach pair may be separated as described above. The present inventionincludes each diastereoisomer of compounds of formula I or II andmixtures thereof.

It will be appreciated that where the active moiety is transformed bythe separation procedures described above, a further step may berequired to convert the transformation product back to the activemoiety.

Certain compounds of formula I or II may exist in different tautomericforms or as different geometric isomers, for example when R₃ and R₄together represent a group of formula ═NR₁₂. The present inventionincludes each tautomer and/or geometric isomer and mixtures thereof.

Certain compounds of formula I or II may exist in zwitterionic form andthe present invention includes each zwitterionic form and mixturesthereof.

The present invention also relates to pharmaceutical compositionscomprising a therapeutically effective amount of a compound of formula Ior II together with a pharmaceutically acceptable diluent or carrier.Such pharmaceutical compositions may be used as neuroprotective agentsto protect against conditions such as stroke and/or for the treatment ofseizures and/or neurological disorders such as epilepsy. Specificcompounds which may be incorporated into the compositions of the presentinvention are the compounds exemplified herein.

As used hereinafter, the term `active compound` denotes one or morecompound or compounds of formula I or II. In therapeutic use, the activecompound may be administered orally, rectally or parenterally,preferably orally. Thus the therapeutic compositions of the presentinvention may take the form of any of the known pharmaceuticalcompositions for such methods of administration. The compositions may beformulated in a manner known to those skilled in the art, to give acontrolled release, for example rapid release or sustained release, ofthe active compound. Pharmaceutically acceptable carriers suitable foruse in such compositions are well known in the art of pharmacy. Thecompositions may contain from about 0.1% to about 99% by weight ofactive compound and are generally prepared in unit dosage form.Preferably the unit dosage of active ingredient is from about 1 mg toabout 1000 mg. The excipients used in the preparation of thesecompositions are the excipients known in the pharmacist's art.

Preferably the compositions of the invention are administered orally inthe known pharmaceutical forms for such administration. Dosage formssuitable for oral administration may comprise tablets, pills, capsules,caplets, granules, powders, elixirs, syrups, solutions and aqueous oroil suspensions.

Solid oral dosage forms, for example tablets, may be prepared by mixingthe active compound with one or more of the following ingredients:

inert diluents, for example lactose, powdered sugar, pharmaceuticalgrade starch, kaolin, mannitol, calcium phosphate or calcium sulphate;

disintegrating agents, for example maize starch, methyl cellulose, agar,bentonite, cellulose, wood products, alginic acid, guar gum, citruspulp, carboxymethylcellulose or sodium lauryl sulphate;

lubricating agents, for example magnesium stearate, boric acid, sodiumbenzoate, sodium acetate, sodium chloride, leucine or polyethyleneglycol;

binders, for example starch, gelatin, sugars (such as sucrose, molassesor lactose), or natural and synthetic gums (such as acacia, sodiumalginate, extract of Irish moss, carboxymethylcellulose,methylcellulose, ethylcellulose, polyethylene glycol, waxes,microcrystalline cellulose or polyvinylpyrrolidone);

colouring agents, for example conventional pharmaceutically acceptabledyes;

sweetening and flavouring agents;

preservatives; and

other optional ingredients known in the art to permit production of oraldosage forms by known methods such as tabletting.

Solid oral dosage forms may be formulated in a manner known to thoseskilled in the art so as to give a sustained release of the compounds ofthe present invention. For example tablets or pills may, if desired, beprovided with enteric coatings by known methods, for example by the useof cellulose acetate phthalate and/or hydroxypropylmethylcellulosephthalate.

Capsules or caplets, for example hard or soft gelatin capsules,containing the active compound with or without added excipients, forexample a fatty oil, may be prepared by conventional means and, ifdesired, provided with enteric coatings in a known manner. The contentsof the capsule or caplet may be formulated using known methods to givesustained release of the active compound. Enteric coated, solid oraldosage forms comprising compositions of the invention may beadvantageous, depending on the nature of the active compound. Variousmaterials, for example shellac and/or sugar, may be present as coatings,or to otherwise modify the physical form of the oral dosage form.

Liquid oral dosage forms comprising compositions of the invention may beelixirs, solutions, suspensions or syrups, for example, aqueoussuspensions containing the active compound in an aqueous medium in thepresence of a non-toxic suspending agent such as sodiumcarboxymethylcellulose; or oily suspensions containing a compound of thepresent invention in a suitable vegetable oil, for example arachis oilor sunflower oil. Liquid oral dosage forms may also comprise sweeteningagents, flavouring agents and/or preservatives.

The active compound may be formulated into granules or powders with orwithout additional excipients. The granules or powders may be ingesteddirectly by the patient or they may be added to a suitable liquidcarrier (for example water) before ingestion. The granules or powdersmay contain disintegrants (for example a pharmaceutically acceptableeffervescent couple formed from an acid and a carbonate or bicarbonatesalt) to facilitate dispersion in the liquid medium.

Each of the above oral dosage forms may conveniently contain from about1 mg to about 1000 mg of the active compound.

Compositions of the invention may be administered rectally in the knownpharmaceutical forms for such administration, for example, suppositorieswith hard fat, semi-synthetic glyceride, cocoa butter or polyethyleneglycol bases.

Compositions of the invention may also be administered parenterally, forexample by intravenous injection, in the known pharmaceutical forms forsuch administration, for example sterile suspensions in aqueous or oilymedia, or sterile solutions in a suitable solvent.

The active compound may also be administered by continuous infusioneither from an external source, for example by intravenous infusion, orfrom a source of the compound placed within the body. Internal sourcesinclude implanted reservoirs containing the compound to be infused whichis continuously released (for example by osmosis) or implants. Implantsmay be liquid, such as a suspension or solution in a pharmaceuticallyacceptable oil of the compound to be infused (for example in the form ofa very sparingly water-soluble derivative such as a dodecanoate salt orester). Implants may be solid in the form of an implanted support (forexample a synthetic resin or waxy material) for the compound to beinfused. The support may be a single body containing all the compound ora series of several bodies each containing part of the compound to bedelivered. The amount of active compound present in an internal sourceshould be such that a therapeutically effective amount of the compoundis delivered over a long period of time.

In some formulations it may be beneficial to use the active compound, orpharmaceutical compositions containing the active compound, in the formof particles of very small size, for example as obtained by fluid energymilling.

In the above compositions the active compound may, if desired, beassociated with other compatible pharmacologically active ingredients.

A further aspect of the present invention provides use of compounds offormula I or II in the preparation of a medicament for the treatment ofseizures and/or neurological disorders such as epilepsy and/or forneuroprotection to protect against conditions such as stroke.

A still further aspect of the present invention provides a method oftreating seizures and/or neurological disorders such as epilepsy and/ora method of neuroprotection to protect against conditions such asstroke, which comprises the administration to patient in need thereof atherapeutically effective amount of compounds of formula I or II and/ora pharmaceutical compositions containing a therapeutically effectiveamount of compounds of formula I or II. Thus compounds of formula I orII are useful for the inhibition of seizures and/or neurologicaldisorders such as epilepsy and/or as neuroprotective agents to protectagainst conditions such as stroke.

Whilst the precise amount of the active compound administered in thetreatments outlined above will depend on a number of factors, forexample the severity of the condition, the age and past medical historyof the patient, and always lies within the sound discretion of theadministering physician, a suitable daily dose of compounds of formula Ior II for administration to human beings, is generally from about 1 mgto about 5000 mg, more usually from about 5 mg to about 1000 mg, givenin a single dose or in divided doses at one or more times during theday. Oral administration is preferred.

Compounds of formula I or II may be used in adjunctive therapy with oneor more other compounds having activity in the treatment of seizuresand/or neurological disorders such as epilepsy and/or as neuroprotectiveagents to protect against conditions such as stroke. It will beappreciated that the term therapy as used herein includes prophylacticuse of compounds of formula I or II and pharmaceutical compositionscontaining compounds of formula I or II, for example as neuroprotectiveagents to protect against conditions such as stroke or to prevent theonset of epileptic seizures. Compounds of formula I or II andpharmaceutical compositions containing compounds of formula I or II maybe used to provide a local and/or systemic therapeutic effect.

The therapeutic activity of compounds of formula I or II has beendemonstrated by means of tests in standard laboratory animals. Suchtests include, for example, the tests of anticonvulsant activity in micedescribed below.

Processes for the preparation of compounds of formula I or II will nowbe described. These processes form a further aspect of the presentinvention.

Compounds of formula I or II, in which R₃ and R₄ are both H and R₅ is Hor alkyl may be prepared by reducing a compound of formula III ##STR4##in which R₅ is H or alkyl, with a reducing agent, for example lithiumaluminium hydride or borane-dimethyl-sulphide complex. Compounds offormula III are known and can be prepared as described in internationalpatent application WO 92/21668.

Compounds of formula I or II in which R₃ and R₄ together are a group offormula ═NR₁₂ may be prepared by the reaction of compounds of formula IV##STR5## with a compound of formula R₁₂ NH₂.

Compounds of formula I or II in which R₃ and R₄ together are a group offormula ═NR₁₂ and R₅ is H may be prepared by the reaction of compoundsof formula V ##STR6## with a compound of formula R₁₂ NH₂.

Compounds of formula I or II in which R₃ and R₄ together are alkoxyiminomay be prepared by the reaction between compounds of formula I or II inwhich R₃ and R₄ together are hydroxyimino with an alkylating agent suchas an alkylsulphate.

Compounds of formula I or II in which R₃ and R₄ are H or alkyl and R₅ isalkyl may be prepared by alkylation of compounds of formula I or II inwhich R₅ is H for example; by using an alkylating agent such as an alkylhalide; or by reductive alkylation with an aldehyde or a ketone andformic acid, or a reducing agent such as sodium cyanoborohydride; or byreducing a compound of formula I or II in which R₅ is a group of formula--COR₁₃.

Compounds of formula I or II in which R₅ is a group of formula --COR₁₃may be prepared by acylation of compounds of formula I or II in whichn=0 or 2 and R₅ is H, for example with an acid chloride of formula R₁₃COCl, an acid anhydride of formula (R₁₃ CO)₂ O or an acid of formula R₁₃CO₂ H.

Compounds of formula I or II in which R₅ is a group of formula--S(O)_(p) R₁₄ may be prepared by the reaction of compounds of formula Ior II in which R₅ is H, with a sulphonylating agent such as a sulphonylchloride of formula R₁₄ SO₂ Cl, or a sulphinylating agent such as asulphinyl chloride of formula R₁₄ SOCl. For example, compounds offormula I or II in which R₅ is --SO₂ Me may be prepared by the reactionof a compound of formula I or II in which R₅ is H with methanesulphonylchloride.

Compounds of formula I or II in which n=1 may be prepared by theoxidation of compounds of formula I or II in which n=0, for exampleusing sodium periodate or 3-chloroperbenzoic acid.

Compounds of formula I or II in which n=2 may be prepared by theoxidation of compounds of formula I or II in which n=0 or 1, for exampleusing peracetic acid or 3-chloroperbenzoic acid.

Compounds of formula IV may be prepared by the reaction of compounds offormula III with reagents such as phosphorus pentasulphide or Lawesson'sreagent [which is the known compound2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4 disulphide].

Compounds of formula V may be prepared by the reaction of compounds offormula III with a chlorinating agent, for example phosphoruspentachloride or phosphoryl chloride.

The anticonvulsant activity of compounds of formula I or II wasdemonstrated by the following pharmacological tests.

Firstly, by observing the ability of the compound of formula I or II toantagonise the myoclonic seizures induced by the administration of(+)-bicuculline. Hereinafter, this test is referred to as `BICM`.

In the BICM experiments groups of female mice in the weight range 25 to30 grammes had free access to food and water until one hour beforeadministration of the compound of formula I or II to be tested. Thecompound to be tested was orally administered at one or more doses in 1%aqueous methylcellulose solution. One hour later (+)-bicuculline at adose of 0.55 mg/kg was administered intravenously into a tail vein. Sucha dose of (+)-bicuculline would generally be expected to induce aseizure in the mice.

During the following two minutes the animals were observed and thepercentage of animals in which seizures had been inhibited was recorded.Thus, the greater the anticonvulsant activity of the compound, thehigher was the percentage recorded in the BICM test. If results at morethan one dose were available, then a value for the dose inhibiting theseizures in 50% of the animals (ED₅₀) was calculated from the regressionstraight line plot of the percentage of animals in which seizures wereinhibited against the dose of the compound of formula I or IIadministered.

The second test of anticonvulsant activity involved observing theability of a compound to inhibit seizures in mice induced by a maximalelectroshock. Hereinafter, this test is referred to as `MESM`.

In the MESM experiments, groups of male mice in the weight range 25 to30 grammes had free access to food and water until one hour beforeadministration of the compound of formula I or II to be tested. Thecompound to be tested was orally administered at one or more doses in 1%aqueous methylcellulose solution. One hour later an electroshock ofduration 1.0 second was administered to the mice through ear clipelectrodes. The electroshock had an intensity of 99 mA, frequency of 50Hz and pulse width of 0.4 ms. Such a shock would generally be expectedto induce a seizure in the mice.

During the following two minutes the animals were observed and thepercentage of animals in which seizures had been inhibited was recorded.Thus, the greater the anticonvulsant activity of the compound, thehigher was the percentage recorded in the MESM test. If results at morethan one dose were available, then a value for the dose inhibitingseizures in 50% of the animals (ED₅₀) was calculated from the regressionstraight line plot of the percentage of animals in which seizures wereinhibited against the dose of the compound of formula I or IIadministered.

The compounds of formula I or II described hereinafter in Examples 1 to31 have been found to have anticonvulsant activity in at least one ofthe BICM and MESM tests.

The invention will now be illustrated by the following non-limitingexamples. The final product of each example was characterised by one ormore of the following; elemental analysis; infra-red spectroscopy;nuclear magnetic resonance spectroscopy; and/or liquid chromatography.Temperatures are given in degrees Celsius.

EXAMPLE 1

6-Chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-one (9.8 g, prepared in asimilar manner to example 11 of international patent application WO92/21668) was added to a stirred solution of lithium aluminium hydride(5.01 g) in dry tetrahydrofuran (400 ml), After the addition, thereaction mixture was heated under reflux for five minutes and cooled.Excess lithium aluminium hydride was decomposed by adding a saturatedaqueous solution of sodium sulphate. The mixture was filtered and thesolvent removed from the filtrate by evaporation. The residue wasdissolved in diethyl ether, acidified with hydrogen chloride gas and theprecipitated 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepinehydrochloride was collected by filtration, and was recrystallised fromethanol. Yield 6.5 g (m.p. 244°-246° C.).

The ED₅₀, in the BICM test described above, for this compound was 8.2mg/kg.

EXAMPLE 2

6-Chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-one (9.8 g, prepared in asimilar manner to example 11 of international patent application WO92/21668) was added to a stirred solution of lithium aluminium hydride(5.01 g) in dry tetrahydrofuran (400 ml). After the addition, thereaction mixture was heated under reflux for five minutes and thencooled. Excess lithium aluminium hydride was decomposed by adding of asaturated aqueous solution of sodium sulphate. The mixture was filteredand the solvent evaporated from the filtrate to give6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine as an oil.

A solution of sodium periodate (3.09 g) in water (25 ml) was addeddropwise with cooling to a stirred solution of6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.88 g, prepared in asimilar manner to that described in the preceding paragraph) indichloromethane (75 ml). The stirring was continued at room temperaturefor 19 hours. Solvent was removed from the mixture by evaporation atreduced pressure. Purification of the residue by flash chromatographyusing dichloromethane/ethanol (95:5) as eluent gave6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide, which wasrecrystallised from ethyl acetate. Yield 2.15 g (m.p. 125°-126° C.).

The ED₅₀, in the BICM test described above, for this compound was 2.7mg/kg.

EXAMPLE 3

6-Fluoro-4,5-dihydro-1,4-benzothiazepin-3 (2H) -one (9 g, prepared in asimilar manner to example 5 of international patent application WO92/21668) was added to a stirred solution of lithium aluminium hydride(5 g) in dry tetrahydrofuran (500 ml). After the addition, the reactionmixture was heated under reflux for ten minutes and cooled. Excesslithium aluminium hydride was decomposed by adding a saturated aqueoussolution of sodium sulphate. The mixture was filtered and the solventremoved from the filtrate by evaporation to give an oil, which wasdissolved in diethyl ether and acidified with hydrogen chloride gas. Theprecipitated 6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepinehydrochloride was collected by filtration and was recrystallised fromethanol. Yield 7.43 g (m.p. 265°-68° C.).

The ED₅₀, in the BICM test described above, for this compound was 17.7mg/kg.

EXAMPLE 4

6-Methyl-4,5-dihydro-1,4-benzothiazepin-3 (2H) -one (6 g, prepared in asimilar manner to example 13 of international patent application WO92/21668) was added to a stirred solution of lithium aluminium hydride(3.38 g) in dry tetrahydrofuran (340 ml). After the addition, thereaction mixture was heated under reflux for ten minutes, and cooled.Excess lithium aluminium hydride was decomposed by adding a saturatedaqueous solution of sodium sulphate. The mixture was filtered and thesolvent was removed from the filtrate by evaporation. The residue wasdissolved in diethyl ether, acidified with hydrogen chloride gas and theprecipitated 6-methyl-2,3,4,5-tetrahydro-1-1,4-benzothiazepinehydrochloride was collected by filtration and was recrystallised fromethanol. Yield 2.87 g (m.p. 248°-250° C.).

The ED₅₀, in the BICM test described above, for this compound was 66.5mg/kg.

EXAMPLE 5

A solution of 6-chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-one (5.33 g,prepared in a similar manner to example 11 of international patentapplication WO 92/21668) in dry dimethylsulphoxide (60 ml) was addedslowly at room temperature to a stirred suspension of sodium hydride(0.6 g) in dimethylsulphoxide (20 ml). After the addition was completed,the mixture was stirred for 30 minutes before adding methyl iodide (6ml) dropwise. The reaction mixture was stirred at room temperature forone hour, water (160 ml) was added and the mixture was extracted withdiethyl ether. The organic layer was washed with water and the solventwas removed by evaporation. Purification of the residue by flashchromatography using dichloromethane/ethyl acetate (9.8:0.2) as eluentgave 6-chloro-4-methyl-4,5-dihydro-1,4-benzothiazepin-3(2H)-one. Yield3.8 g (m.p. 122°-125° C.).

6-Chloro-4-methyl-4,5-dihydro-1,4-benzothiazepin-3(2H)-one (3.8 g) wasadded to a stirred solution of lithium aluminium hydride (1.92 g) in drytetrahydrofuran (160 ml). After the addition, the reaction was heatedunder reflux for 15 minutes and cooled. Excess lithium aluminium hydridewas decomposed by adding a saturated aqueous solution of sodiumsulphate. The mixture was filtered and the solvent was removed from thefiltrate by evaporation. Purification of the residue by flashchromatography using dichloromethane/ethanol (9.5:0.5) as eluent gave anoil (2.62 g) which was dissolved in diethyl ether and acidified withhydrogen chloride gas. The precipitated6-chloro-4-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine hydrochloridewas collected by filtration and was recrystallised from ethanol/diethylether. Yield 2.38 g (m.p. 209°-211° C.).

In the BICM test described above, a dosage of 100 mg/kg of this compoundinhibited 50% of the mice tested from seizures.

EXAMPLE 6

4,5-Dihydro-1,4-benzothiazepin-3(2H)-one (12 g, prepared in a similarmanner to example 1 of international patent application WO 92/21668) wasadded to a stirred solution of lithium aluminium hydride (6.3 g) in drytetrahydrofuran (400 ml). After the addition, the reaction mixture washeated under reflux for ten minutes and cooled. Excess of lithiumaluminium hydride was decomposed by adding a saturated aqueous solutionof sodium sulphate. The mixture was filtered and the solvent was removedfrom the filtrate by evaporation to give2,3,4,5-tetrahydro-1,4-benzothiazepine as an oil which was used withoutfurther purification. Yield 9.4 g.

A mixture of 2,3,4,5-tetrahydro-1,4-benzothiazepine (4.56 g), formicacid (20 ml) and toluene (60 ml) was heated under reflux at 90° C. forfour hours and then at 120° C. for a further three hours. The solventwas removed from the mixture by evaporation at reduced pressure.Purification of the residue by flash chromatography usingdichloromethane as eluent gave4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which wasrecrystallised from hexane. Yield 3.73 g (m.p. 84°-87° C.).

The ED₅₀, in the BICM test described above, for this compound was 17.9mg/kg.

EXAMPLE 7

A solution of 2,3,4,5-tetrahydro-1,4-benzothiazepine (1.5 g, prepared asdescribed in the first paragraph of Example 6 above) in acetic anhydride(15 ml) was stirred at room temperature for one hour. The reactionmixture was poured into ice and extracted with dichloromethane. Theorganic layer was dried and the solvent removed by evaporation to give4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine [a compound known as aFriedel Crafts catalyst from Example 46 of EP 368063 (Bayer)]. Theproduct was recrystallised from hexane. Yield 1.55 g (m.p. 69°-70° C.).

The ED₅₀, in the BICM test described above, for this compound was 65.7mg/kg.

EXAMPLE 8

A solution of 3-chloroperbenzoic acid (1.03 g) in dichloromethane (100ml) was added dropwise with cooling from 0° C. to -2° C. to a stirredsolution of 4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.03 g,prepared as Example 7 above) in dichloromethane (50 ml). The reactionmixture was stirred for 15 minutes, then washed with water, dried andthe solvent was removed by evaporation at reduced pressure. Purificationof the residue by flash chromatography using dichloromethane/ethanol(9:1) as eluent gave 4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide, which was recrystallised from ethyl acetate. Yield 0.67 g (m.p.156°-157° C.).

The ED₅₀, in the BICM test described above, for this compound was 37.8mg/kg.

EXAMPLE 9

A solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.6 g,prepared in a similar manner to its hydrochloride, Example 1 above) inacetic anhydride (15 ml) was stirred at room temperature for one hour.The reaction mixture was poured into ice and extracted withdichloromethane. The organic layer was dried and the solvent was removedby evaporation to give4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine, which wasrecrystallised from hexane. Yield 1.68 g (m.p. 79°-81° C.).

The ED₅₀, in the BICM test described above, for this compound was 4.6mg/kg.

The ED₅₀, in the MESM test described above, for this compound was 48.5mg/kg.

EXAMPLE 10

A solution of 3-chloroperbenzoic acid (1.14 g) in dichloromethane (100ml) was added dropwise with cooling from 0° C. to -2° C. to a stirredsolution of 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine(1.34 g, prepared as Example 9 above) in dichloromethane (50 ml). Thereaction mixture was stirred for 15 minutes, washed with water, driedand the solvent was removed by evaporation at reduced pressure.Purification of the residue by flash chromatography usingdichloromethane/ethanol (95:5) as eluent gave4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide, whichwas recrystallised from ethyl acetate. Yield 1.15 g (m.p. 119°-121° C.).

The ED₅₀, in the BICM test described above, for this compound was 22.6mg/kg.

The ED₅₀, in the MESM test described above, for this compound was 52.8mg/kg.

EXAMPLE 11

A solution of 6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.04 g,prepared in a similar manner to its hydrochloride, Example 3 above) inacetic anhydride (22 ml) was stirred at room temperature for one hour.The reaction mixture was poured into ice and extracted withdichloromethane. The organic layer was dried and the solvent removed byevaporation. Purification of the residue by flash chromatography usingdichloromethane/ethanol (97:3) as eluent gave4-acetyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine as an oil.Yield 1.7 g.

The ED₅₀, in the BICM test described above, for this compound was 21.5mg/kg.

EXAMPLE 12

A solution of 6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.91 g,prepared in a similar manner to its hydrochloride, Example 4 above) inacetic anhydride (10 ml) was stirred at room temperature for one hour.The reaction mixture was poured into ice and extracted withdichloromethane. The organic layer was dried and the solvent removed byevaporation to give4-acetyl-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which wasrecrystallised from hexane. Yield 0.93 g (m.p. 71°-73° C.).

The ED₅₀, in the BICM test described above, for this compound was 49.4mg/kg.

In the MESM test described above, a dosage of 100 mg/kg of this compoundinhibited 50% of the mice tested from seizures.

EXAMPLE 13

A solution of propionyl chloride (2.39 g) in dichloromethane (50 ml) wasadded dropwise at room temperature to a stirred solution of2,3,4,5-tetrahydro-1,4-benzothiazepine (8.58 g, prepared as described inthe first paragraph of Example 6 above) in dichloromethane (100 ml). Thereaction mixture was stirred at room temperature for 45 minutes, washedwith water, dried and the solvent was removed by evaporation.Purification of the residue by flash chromatography usingdichloromethane/ethanol (98:2) as eluent gave4-propionyl-2,3,4,5-tetrahydro-1,4-benzothiazepine as an oil. Yield 2.9g.

The ED₅₀, in the BICM test described above, for this compound was 48.1mg/kg.

EXAMPLE 14

A solution of propionyl chloride (0.92 g) in dichloromethane (10 ml) wasadded dropwise at room temperature to a stirred solution of6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.99 g, prepared in asimilar manner to its hydrochloride, Example 1 above) and triethylamine(1.01 g) in dichloromethane (50 ml). The reaction mixture was stirred atroom temperature for 30 minutes, washed with water, dried and thesolvent was removed by evaporation. Purification of the residue by flashchromatography using dichloromethane as eluent gave6-chloro-4-propionyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which wasrecrystallised from hexane. Yield 1.14 g (m.p. 55°-57° C.).

The ED₅₀, in the BICM test described above, for this compound was 44.7mg/kg.

EXAMPLE 15

A solution of benzoyl chloride (3.93 g) in dichloromethane (50 ml) wasadded dropwise at room temperature to a stirred solution of6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (4.5 g, prepared in asimilar manner to its hydrochloride, Example 1 above) and triethylamine(2.82 g) in dichloromethane (100 ml). The reaction mixture was stirredat room temperature for 15 minutes, washed with water, dried and thesolvent was removed by evaporation. Purification of the residue by flashchromatography using dichloromethane as eluent gave4-benzoyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine, which wasrecrystallised from ethanol/water. Yield 5.93 g (m.p. 64°-72° C.).

The ED₅₀, in the BICM test described above, for this compound was 49.2mg/kg.

EXAMPLE 16

A solution of methanesulphinyl chloride (0.98 g) in dichloromethane (10ml) was added dropwise at room temperature to a stirred solution of6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.99 g, prepared in asimilar manner to its hydrochloride, Example 1 above) and triethylamine(1.01 g) in dichloromethane (50 ml). The reaction mixture was stirred atroom temperature for one hour, washed with water, dried and the solventwas removed by evaporation. Purification of the residue by flashchromatography using dichloromethane/ethanol (98:2) as eluent gave6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, whichwas recrystallised from ethylacetate/hexane. Yield 2.1 g (m.p. 82°-84°C.).

The ED₅₀, in the BICM test described above, for this compound was 19.6mg/kg.

EXAMPLE 17

A solution of methanesulphonyl chloride (3.3 g) in dichloromethane (15ml) was added dropwise at room temperature to a stirred solution of2,3,4,5-tetrahydro-1,4-benzothiazepine (4.8 g, prepared as described inthe first paragraph of Example 6 above) and triethylamine (2.9 g) indichloromethane (100 ml). The reaction mixture was stirred at roomtemperature for one hour, washed with water, dried and the solvent wasremoved by evaporation. Purification of the residue by flashchromatography using dichloromethane as eluent gave4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine which wasrecrystallised from hexane. Yield 3 g. (m.p. 98°-100° C.).

The ED₅₀, in the BICM test described above, for this compound was 40.8mg/kg.

The ED₅₀, in the MESM test described above, for this compound was 51.6mg/kg.

EXAMPLE 18

A solution of 3-chloroperbenzoic acid (1.4 g) in dichloromethane (200ml) was added dropwise with cooling from 0° C. to -2° C. to a stirredsolution of 4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (2g, prepared as Example 17 above) in dichloromethane (50 ml). Thereaction mixture was stirred for 15 minutes, washed with water, driedand the solvent was removed by evaporation at reduced pressure.Purification of the residue by flash chromatography usingdichloromethane/ethanol (95:5) as eluent gave4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide, whichwas recrystallised from ethanol. Yield 1.65 g (m.p. 195°-197° C.).

The ED₅₀, in the BICM test described above, for this compound was 27.4mg/kg.

EXAMPLE 19

A solution of methanesulphonyl chloride (3.43 g) in dichloromethane (30ml) was added dropwise at room temperature to a stirred solution of6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (5.2 g, prepared in asimilar manner to its hydrochloride, Example 1 above) and triethylamine(3.03 g, 0.03 ml) in dichloromethane (100 ml). The reaction mixture wasstirred at room temperature for one hour, washed with water, dried andthe solvent was removed by evaporation. Purification of the residue byflash chromatography using dichloromethane as eluent gave6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, whichwas recrystallised from hexane. Yield 6.06 g (m.p. 85°-86° C.).

The ED₅₀, in the BICM test described above, for this compound was 41.3mg/kg.

The ED₅₀, in the MESM test described above, for this compound was 19.5mg/kg.

EXAMPLE 20

A solution of 3-chloroperbenzoic acid (2.26 g) in dichloromethane (150ml) was added dropwise with cooling from 0° C. to -2° C. to a stirredsolution of6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (3.05g, prepared as Example 19 above) in dichloromethane (100 ml). Thereaction mixture was stirred for 15 minutes, washed with water anddried, and the solvent was removed by evaporation at reduced pressure.Purification of the residue by flash chromatography usingdichloromethane/ethanol (95:5) as eluent gave6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide, which was recrystallised from ethyl acetate. Yield 2.86 g (m.p.167°-169° C.).

The ED₅₀, in the BICM test described above, for this compound was 36.2mg/kg.

The ED₅₀, in the MESM test described above, for this compound was 31.9mg/kg.

EXAMPLE 21

A solution of methanesulphonyl chloride (1.83 g) in dichloromethane (30ml) was added dropwise at room temperature to a stirred solution of6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.65 g, prepared in asimilar manner to its hydrochloride, Example 3 above) and triethylamine(1.6 g) in dichloromethane (60 ml). The reaction mixture was stirred atroom temperature for 20 minutes, washed with water, dried and thesolvent was removed by evaporation. Purification of the residue by flashchromatography using dichloromethane as eluent gave6-fluoro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, whichwas recrystallised from hexane. Yield 3.3 g (m.p. 115°-117° C.).

The ED₅₀, in the BICM test described above, for this compound was 33.8mg/kg.

The ED₅₀, in the MESM test described above, for this compound was 30.5mg/kg.

EXAMPLE 22

A solution of methanesulphonyl chloride (1.69 g) in dichloromethane (20ml) was added dropwise at room temperature to a stirred solution to6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (2 g, prepared in asimilar manner to its hydrochloride, Example 4 above) and triethylamine(1.51 g) in dichloromethane (30 ml). The reaction mixture was stirred atroom temperature for one hour, washed with water, dried and the solventwas removed by evaporation. Purification of the residue by flashchromatography using dichloromethane as eluent gave6-methyl-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, whichwas recrystallised from ethyl acetate/hexane. Yield 2.48 g (m.p.128°-130° C.).

The ED₅₀, in the BICM test described above, for this compound was 116.3mg/kg.

The ED₅₀, in the MESM test described above, for this compound was 102.2mg/kg.

EXAMPLE 23

A solution of ethanesulphonyl chloride (3.8 g) in dichloromethane (50ml) was added dropwise at room temperature to a stirred solution of2,3,4,5-tetrahydro-1,4-benzothiazepine (4.29 g, prepared as described inthe first paragraph of Example 6 above) in dichloromethane (100 ml). Thereaction mixture was stirred at room temperature for one hour, washedwith water, dried and the solvent was removed by evaporation.Purification of the residue by flash chromatography usingtrichloromethane as eluent gave4-ethylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which wasrecrystallised from hexane. Yield 4.25 g (m.p. 78°-80° C.).

The ED₅₀, in the MESM test described above, for this compound was 22.3mg/kg.

EXAMPLE 24

A solution of ethanesulphonyl chloride (1.28 g) in dichloromethane (10ml) was added dropwise at room temperature to a stirred solution of6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.99 g, prepared in asimilar manner to its hydrochloride, Example 1 above) and triethylamine(1.01 g) in dichloromethane (50 ml). The reaction mixture was stirred atroom temperature for one hour, washed with water, dried and the solventwas removed by evaporation. Purification of the residue by flashchromatography using dichloromethane as eluent gave4-ethylsulphonyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine, whichwas recrystallised from ethyl acetate/hexane. Yield 2.53 g (m.p.126°-128° C.).

The ED₅₀, in the BICM test described above, for this compound was 90.4mg/kg.

The ED₅₀, in the MESM test described above, for this compound was 35.1mg/kg.

EXAMPLE 25

A stirred mixture of 4,5-dihydro-1,4-benzothiazepin-3(2H)-one (1.79 g,prepared as example 1 of international patent application WO 92/21668)and Lawesson's reagent (2.22 g) in dry toluene (100 ml) was heated at100° C. for three hours. The mixture was allowed to cool to roomtemperature. The precipitated solid was collected by filtration, washedwith toluene and dried to give4,5-dihydro-1,4-benzothiazepin-3(2H)-thione. Yield 1.78 g (m.p.215°-219° C.).

A mixture of 4,5-dihydro-1,4-benzothiazepin-3(2H)-thione (1.56 g),hydroxylamine hydrochloride (0.83 g) and sodium acetate (0.98 g) in dryethanol (100 ml) was heated under reflux for three hours. The mixturewas cooled, and the precipitated solid was collected by filtration andwashed with water. Purification of the precipitate by flashchromatography using dichloromethane/ethanol (95:5) as eluent gave3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, which wasrecrystallised from ethanol. Yield 1.2 g (m.p. 208°-210° C.).

The ED₅₀, in the BICM test described above, for this compound was 31.5mg/kg.

EXAMPLE 26

A stirred mixture of 6-chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-one(4.27 g, prepared as example 11 of international patent application WO92/21668) and Lawesson's reagent (4.90 g) in dry toluene (170 ml) washeated under reflux for one hour. The reaction mixture was cooled toroom temperature and the precipitated6-chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-thione was collected byfiltration, washed with toluene and dried. Yield 4.16 g (m.p. 210°-212°C.).

A stirred mixture of6-chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-thione (3.90 g),hydroxylamine hydrochloride (1.77 g) and sodium acetate (2.09 g) in dryethanol (175 ml) was heated under reflux for one hour. The reactionmixture was cooled and the precipitated6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine wascollected by filtration, washed with water and recrystallised fromethanol. Yield 2.6 g (m.p. 180°-183° C.).

The ED₅₀, in the BICM test described above, for this compound was 5.0mg/kg.

EXAMPLE 27

A stirred mixture of 6-methyl-4,5-dihydro-1,4-benzothiazepin-3(2H)-one(3.26 g, prepared in a similar manner to example 13 of internationalpatent application WO 92/21668) and Lawesson's reagent (3.93 g) in drytoluene (170 ml) was heated under reflux for one hour. The reactionmixture was cooled to room temperature and the precipitated6-methyl-4,5-dihydro-1,4-benzothiazepin-3(2H)-thione was collected byfiltration, washed with toluene and dried. Yield 3.30 g (m.p. 228°-230°C.).

A stirred mixture of6-methyl-4,5-dihydro-1,4-benzothiazepin-3(2H)-thione (3.13 g),hydroxylamine hydrochloride (1.56 g) and sodium acetate (1.84 g) in dryethanol (175 ml) was heated under reflux for one hour. The reactionmixture was cooled and the precipitated3-hydroxyimino-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine wascollected by filtration, washed with water and recrystallised fromethanol. Yield 2.23 g (m.p. 188°-190° C.).

The ED₅₀, in the BICM test described above, for this compound was 20.1mg/kg.

EXAMPLE 28

Dimethylsulphate (1.26 g) was added dropwise to a vigorously stirredsuspension of 3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine (2g, prepared in a similar manner to Example 25 above) in a mixture of a10% aqueous solution of sodium hydroxide (4 ml) and ethanol (150 ml).The reaction mixture was kept at room temperature for 24 hours and thenextracted with dichloromethane. The organic layer was dried and thesolvent was removed by evaporation. Purification of the solid residue byflash chromatography using dichloromethane as eluent gave3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, which wasrecrystallised from hexane. Yield 1.51 g (m.p. 101°-102° C.).

The ED₅₀, in the BICM test described above, for this compound was 58.2mg/kg.

EXAMPLE 29

A 10% aqueous solution of sodium hydroxide (4 ml) was added to asuspension of6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.29 g,prepared as Example 26 above) in ethanol (150 ml). After 15 minutesdimethylsulphate (1.33 g) was added dropwise to the mixture. Thereaction mixture was stirred at room temperature for 22 hours and thenthe solvent was removed by evaporation at reduced pressure. Purificationof the residue by chromatography on a silica gel support usingdichloromethane followed by dichloromethane/ethanol (97:3) as successiveeluents gave6-chloro-3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, whichwas recrystallised from n-hexane. Yield 1.21 g (m.p. 120°-121° C.).

In the BICM test described above, a dosage of 100 mg/kg of this compoundinhibited 50% of the mice tested from seizures.

EXAMPLE 30

A mixture of 4,5-dihydro-1,4,-benzothiazepine-3(2H)-one (5.37 g,prepared as example 1 of international patent application WO 92/21668)and phosphorus pentachloride (6.3 g) in dry toluene was heated at 50° C.for two hours. The precipitated product was collected by filtration,washed with toluene and dried to give3-chloro-2,5-dihydro-1,4-benzothiazepine. Yield 5.2 g (m.p. 164°-168°C.). This crude product was used in the next step without furtherpurification.

3-Chloro-2,5-dihydro-1,4-benzothiazepine (5 g) and a 33% solution ofmethylamine in absolute ethanol (150 ml) were heated under reflux forone hour. The mixture was cooled and filtered. Purification of theresidue by flash chromatography using ethyl acetate/ethanol (1:1) aseluent gave 3-methylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, whichwas recrystallised from ethanol. Yield 0.51 g (m.p. 278°-280° C.).

The ED₅₀, in the BICM test described above, for this compound was 20.8mg/kg.

EXAMPLE 31

Phosphorus pentachloride (5.84 g) was added in portions to a stirredsuspension of 6-chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-one (6.0 g,prepared as example 1 of international patent application WO 92/21668)in dry toluene (450 ml). The reaction mixture was then heated in an oilbath at 50°-60° C. for 51/2 hours. After cooling, the crude precipitateof 3,6-dichloro-2,5-dihydro-1,4-benzothiazepine was collected byfiltration, and washed with toluene. Yield 4.85 g. This crude productwas used in the next step without further purification.

A solution of aniline (4.8 ml) in dry ethanol (10 ml) was added dropwiseat room temperature to a stirred solution of3,6-dichloro-2,5-dihydro-1,4-benzothiazepine (2.5 g) in dry ethanol (65ml). The reaction mixture was heated under reflux for 91/2 hours, cooledto room temperature, filtered and the solvent was removed from thefiltrate by evaporation at reduced pressure. The oily residue wasseparated into fractions by chromatography on a silica gel support usingchloroform/ethanol (50:1) as eluent. Purification of those fractionscontaining the product by flash chromatography using ethylacetate/hexane (2:3) as eluent gave6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, which wasrecrystallised from ethyl acetate/hexane. Yield 0.27 g (m.p. 150°-152°C.).

The ED₅₀, in the BICM test described above, for this compound was 16.3mg/kg.

We claim:
 1. A compound of formula I ##STR7## wherein n is 0, 1 or 2;R₁,R₂, R₆ and R₇ are H; R₃ and R₄ are independently H or methyl; ortogether are selected from the group consisting of imino, methylimino,phenylimino, hydroxyimino and methoxyimino; R₅ is H or methyl, or whenR₃ and R₄ are independently H or methyl, R₅ is selected from the groupconsisting of formyl, acetyl, propionyl, benzoyl, methylsulphinyl,methylsulphonyl and ethylsulphonyl; R₈ is selected from the groupconsisting of H, methyl, fluoro and chloro; and R₉, R₁₀ and R₁₁ are eachH, a stereoisomer thereof or a pharmaceutically acceptable salt thereof;with the provisos thati) at least one of R₁ to R₁₁ is other than H; ii)when n is 0 and R₁ to R₄ and R₆ to R₁₁ are each H, then R₅ is other thanbenzoyl or acetyl; and iii) when n is 0, 1 or 2, and R₁ to R₃ and R₅ toR₁₁ are each H, then R₄ is other than methyl.
 2. A compound as claimedin claim 1, wherein the compound is selectedfrom:6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;4-acetyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide;4-ethylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;3-hydroxyimino-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;3-methylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine; and6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, astereoisomer thereof, or a pharmaceutically acceptable salt thereof. 3.A compound as claimed in claim 1, wherein the compound is selectedfrom:6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine; and6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, astereoisomer thereof, or a pharmaceutically acceptable salt thereof. 4.A compound as claimed in claim 1, wherein the compound is selectedfrom:4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide; and6-fluoro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, astereoisomer thereof, or a pharmaceutically acceptable salt thereof. 5.A compound as claimed in claim 1, wherein the compoundsis:4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine, astereoisomer thereof, or a pharmaceutically acceptable salt thereof. 6.A pharmaceutical composition comprising a compound of formula I ##STR8##wherein n=0, 1 or 2;R₁ and R₂ independently are H or alkyl of 1 to 4carbon atoms which is unsubstituted or substituted by at least one haloatom; R₃ and R₄ independently are H or alkyl of 1 to 4 carbon atoms; ortogether represent a group of formula ═NR₁₂ where R₁₂ is selected fromthe group consisting of H, hydroxy, alkyl of 1 to 4 carbon atoms, phenyland alkoxy of 1 to 4 carbon atoms; wherein each alkyl, phenyl and alkoxyis unsubstituted or substituted by at least one halo atom; R₅ isselected from the group consisting of (a) H, (b) alkyl of 1 to 4 carbonatoms, (c) a group of formula --COR₁₃ wherein R₁₃ is selected from thegroup consisting of H, alkyl of 1 to 4 carbon atoms and phenyl, when R₃and R₄ independently are H or alkyl of 1 to 4 carbon atoms which isunsubstituted or substituted by at least one halo atom and (d) a groupof formula --S(O)_(p) R₁₄ in which p=1 or 2 and R₁₄ is alkyl of 1 to 4carbon atoms or phenyl, when R₃ and R₄ independently are H or alkyl of 1to 4 carbon atoms which is unsubstituted or substituted by one or morehalo atom; wherein each alkyl and phenyl is unsubstituted or substitutedby at least one halo atom; R₆ and R₇ independently are H; R₈ to R₁₁independently are selected from the group consisting of H, halo, cyano,nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms,alkanoyl of 1 to 4 carbon atoms, carboxy, alkanoyloxy of 1 to 4 carbonatoms, carbamoyl which is unsubstituted or substituted with alkyl of 1to 4 carbon atoms and sulphamoyl which is unsubstituted or substitutedwith alkyl of 1 to 4 carbon atoms; wherein each alkyl, alkoxy, alkanoylor alkanoyloxy is unsubstituted or substituted by at least one haloatom, a stereoisomer thereof, or a pharmaceutically acceptable saltthereof, with the proviso that:(i) when n=0; at least one of R₁ to R₁₁is other than H; together with a pharmaceutically acceptable diluent orcarrier.
 7. A pharmaceutical composition as claimed in claim 6,whereinn=0 or 1; R₁ and R₂ are independently H or methyl; R₃ and R₄ areindependently H or methyl; or together are selected from the groupconsisting of imino, methylimino, phenylimino, hydroxyimino andmethoxyimino; R₅ is H or methyl, or when R₃ and R₄ are independently Hor methyl, R₅ is selected from the group consisting of formyl, acetyl,propionyl, benzoyl, methylsulphinyl, methylsulphonyl and ethylsulphonyl;R₆ and R₇ independently are H; and one of R₈ to R₁₁ is (a) H, (b)fluoro, (c) chloro, (d) bromo, (e) iodo, (f) methyl which isunsubstituted or substituted with one or more halo, (g) methoxy which isunsubstituted or substituted by one or more halo, (h) nitro, (i) cyano,(j) carboxy, (k) acetyl, (1) dimethylcarbamoyl and (m)dimethylsulphamoyl; and the remainder of R₈ to R₁₁ are H, a stereoisomerthereof, or a pharmaceutically acceptable salt thereof.
 8. Apharmaceutical composition as claimed in claim 6, whereinn=0 or 1; R₁,R₂, R₆ and R₇ are all H; R₃ and R₄ are each H, or together are selectedfrom the group consisting of methylimino, phenylimino, hydroxyimino ormethoxyimino; R₅ is H or methyl, or when R₃ and R₄ are each H, R₅ isselected from the group consisting of formyl, acetyl, propionyl,benzoyl, methylsulphinyl, methylsulphonyl and ethylsulphonyl; R₈ isselected from the group consisting of H, methyl, fluoro and chloro; andR₉ to R₁₁ are all H, a stereoisomer thereof, or a pharmaceuticallyacceptable salt thereof.
 9. A pharmaceutical composition as claimed inclaim 6, wherein the compound is selectedfrom:6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;6-chloro-4-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;4-acetyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;4-acetyl-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;4-propionyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;6-chloro-4-propionyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;4-benzoyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide; 6-fluoro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;6-methyl-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;4-ethylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;6-chloro-4-ethylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;3-hydroxyimino-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;6-chloro-3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;3-methylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine; and6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, astereoisomer thereof or a pharmaceutically acceptable salt thereof. 10.A pharmaceutical composition as claimed in claim 6, wherein the compoundis present in the composition in an amount from about 1 mg to about 1000mg.
 11. A method of treating seizures in a patient in need of suchtreatment, comprising administering to the patient a seizure-treatingeffective amount of a pharmaceutical composition as claimed in claim 6.12. A method as claimed in claim 11, wherein the pharmaceuticalcomposition is administered at a daily dose of from about 1 mg to about5000 mg.
 13. A method as claimed in claim 11, wherein the pharmaceuticalcomposition is administered at a daily dose of from about 5 mg to about1000 mg.
 14. A method of treating a neurological disorder in a patientin need of such treatment, comprising administering to the patient aneurological-disorder-treating effective amount of a pharmaceuticalcomposition as claimed in claim
 6. 15. A method as claimed in claim 14,wherein the pharmaceutical composition is administered at a daily doseof from about 1 mg to about 5000 mg.
 16. A method as claimed in claim14, wherein the pharmaceutical composition is administered at a dailydose of from about 5 mg to about 1000 mg.
 17. A method of treatingepilepsy in a patient in need of such treatment, comprisingadministering to the patient a epilepsy-treating effective amount of apharmaceutical composition as claimed in claim
 6. 18. A method asclaimed in claim 17, wherein the pharmaceutical composition isadministered at a daily dose of from about 1 mg to about 5000 mg.
 19. Amethod as claimed in claim 17, wherein the pharmaceutical composition isadministered at a daily dose of from about 5 mg to about 1000 mg.
 20. Amethod of neuroprotection in a patient in need of such protection,comprising administering to the patient a neuroprotecting effectiveamount of a pharmaceutical composition as claimed in claim
 6. 21. Amethod as claimed in claim 20, wherein the pharmaceutical composition isadministered at a daily dose of from about 1 mg to about 5000 mg.
 22. Amethod as claimed in claim 20, wherein the pharmaceutical composition isadministered at a daily dose of from about 5 mg to about 1000 mg.
 23. Amethod of protecting against stroke in a patient in need of suchprotection, comprising administering to the patient a stroke-protectingeffective amount of a pharmaceutical composition as claimed in claim 6.24. A method as claimed in claim 23, wherein the pharmaceuticalcomposition is administered at a daily dose of from about 1 mg to about5000 mg.
 25. A method as claimed in claim 23, wherein the pharmaceuticalcomposition is administered at a daily dose of from about 5 mg to about1000 mg.
 26. A method of treating seizures in a patient in need of suchtreatment, comprising administering to the patient a seizure-treatingeffective amount of a compound as claimed in claim
 1. 27. A method oftreating a neurological disorder in a patient in need of such treatment,comprising administering to the patient a neurological-disorder-treatingeffective amount of a compound as claimed in claim
 1. 28. A method oftreating epilepsy in a patient in need of such treatment, comprisingadministering to the patient a epilepsy-treating effective amount of acompound as claimed in claim
 1. 29. A method of neuroprotection in apatient in need of such protection, comprising administering to thepatient a neuroprotecting effective amount of a compound as claimed inclaim
 1. 30. A method of protecting against stroke in a patient in needof such protection, comprising administering to the patient astroke-protecting effective amount of a compound as claimed in claim 1.31. A process for preparing a compound as claimed in claim 1, comprisingreducing a compound of formula III ##STR9## wherein n is 0, 1 or 2;R₁,R₂, R₆ and R₇ are all H; R₅ is H; R₈ is selected from the groupconsisting of H, methyl, fluoro and chloro; and R₉, R₁₀ and R₁₁ are eachH, a stereoisomer thereof or a pharmaceutically acceptable salt thereof,with a reducing agent to produce as a product a compound as claimed inclaim 1 wherein R₃ and R₄ are each H.
 32. A process as claimed in claim31, further comprising acylating the product with an acid chloride, acidanhydride or acid to produce a compound as claimed in claim 1 wherein R₃and R₄ are each H, and wherein R₅ is a group of formula --COR₁₃ whereinR₁₃ is selected from the group consisting of H, an alkyl of 1 or 2carbon atoms and phenyl.